Medicinal Chemistry Research

, Volume 23, Issue 3, pp 1378–1386 | Cite as

Synthesis and leishmanicidal activity of cinnamic acid esters: structure–activity relationship

  • Elver Otero
  • Sara M. Robledo
  • Santiago Díaz
  • Miguel Carda
  • Diana Muñoz
  • Julian Paños
  • Ivan D. Vélez
  • Wilson CardonaEmail author
Original Research


Several cinnamic acid esters were obtained via Fischer esterification of cinnamic acids derivatives with aliphatic alcohols. Structures of the products were elucidated by spectroscopic analysis. The synthesized compounds were evaluated for antileishmanial activity against L. (V) panamensis amastigotes and cytotoxic activity was evaluated against mammalian U-937 cells. The compounds 11, 1517, and 23, were active against Leishmania parasite and although toxic for mammalian cells, they still are potential candidates for antileishmanial drug development. A SAR analysis indicates that first, while smaller alkyl chains lead to higher selectivity indices (10, 11 vs. 1217); second, the degree of oxygenation is essential for activity, primarily in positions 3 and 4 (17 vs. 1820 and 22); and third, hydroxyl groups increase both activity and cytotoxicity (14 vs. 23). On the other hand, the presence of a double bond in the side chain is crucial for cytotoxicity and leishmanicidal activity (12 vs. 21). However, further studies are required to optimize the structure of the promising molecules and to validate the in vitro activity against Leishmania demonstrated here with in vivo studies.


Leishmaniasis Antiprotozoal Caffeic acid Cinnamic acid ester 



The authors thank Dr. Javier Garcés for his help in this study. We acknowledge the support by the Universidad de Antioquia (Estrategia de Sostenibilidad 2013–2014 and CIDEPRO) and Colciencias (contract No. 357-2011).


  1. Almajano MP, Carbó R, Delgado ME, Gordon MH (2007) Effect of pH on the antimicrobial activity and oxidative stability of oil-in-water emulsions containing caffeic acid. J Food Sci 72:C258–C263CrossRefPubMedGoogle Scholar
  2. Aponte J, Castillo D, Estevez Y, Gonzalez G, Arevalo J, Hammonda G, Sauvain M (2010) In vitro and in vivo anti-Leishmania activity of polysubstituted synthetic chalcones. Bioorg Med Chem Lett 20:100–103CrossRefPubMedGoogle Scholar
  3. Barrett M, Gilbert I (2002) Perspectives for new drugs against trypanosomiasis and leishmaniasis. Curr Top Med Chem 2:471–482CrossRefPubMedGoogle Scholar
  4. Bowles BL, Miller AJ (1994) Caffeic Acid Activity against Clostridium botulinum Spores. J Food Sci 59:905–908CrossRefGoogle Scholar
  5. Brenzan MA, Vaturu C, Dias B, Ueda T, Young MC, Goncalves A et al (2008) Structure–activity relationship of (-) mammea A/BB derivatives against Leishmania amazonensis. Biomed Pharmacother 62:651–658CrossRefPubMedGoogle Scholar
  6. Buck S, Hardouin C, Ichikawa S, Soenen D, Gauss C, Hwang I, Swingle M, Bonness K, Honkanen R, Boger D (2003) Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition. J Am Chem Soc 125:15694–15695CrossRefPubMedGoogle Scholar
  7. Cabanillas B, Le Lamer AC, Castillo D, Arevalo J, Rojas R, Odonne G, Bourdy G, Moukarzel B, Sauvain M, Fabre N (2010) Caffeic acid esters and lignans from Piper sanguineispicum. J Nat Prod 73:1884–1890CrossRefPubMedGoogle Scholar
  8. Cardona W, Saez J (2011) Antiprotozoal activity of α, β-unsaturated δ-lactones: promising compounds for the development of new therapeutic alternatives. Trop J Pharm Res 10:671–680Google Scholar
  9. Cardona W, Quiñones W, Robledo S, Vélez I, Murga J et al (2006) Antiparasite and antimycobacterial activity of passifloricin analogues. Tetrahedron 62:4086–4092CrossRefGoogle Scholar
  10. Croft S, Coombs G (2003) Leishmaniasis-current chemotherapy and recent advances in the search for novel drugs. Trends Parasitol 19:502–508CrossRefPubMedGoogle Scholar
  11. Da Cunha FM, Duma D, Assreuy J, Buzzi FC, Niero R, Campos MM, Calixto JB (2004) Caffeic acid derivatives: in vitro and in vivo anti-inflammatory properties. Free Radic Res 38:1241–1253CrossRefPubMedGoogle Scholar
  12. De Campos F, Franzoi C, Antonini G, Fracasso M, Cechinel V, Yunes R, Niero R (2009) Antinociceptive properties of caffeic acid derivatives in mice. Eur J Med Chem 44:4596–4602CrossRefGoogle Scholar
  13. De Fatima A, Kohn L, Antonio M, De Carvalho J, Pilli R (2006) Cytotoxic activity of (S)-goniothalamin and analogues against human cancer cells. Bioorg Med Chem 14:622–631CrossRefPubMedGoogle Scholar
  14. De P, Baltas M, Bedos-Belval F (2011) Cinnamic acid derivatives as anticancer agents-a review. Curr Med Chem 18:1672–1703CrossRefPubMedGoogle Scholar
  15. Desjeux P (2004) Leishmaniasis: current situation and new perspectives. Comp Immunol Microbiol Infect Dis 27:305–318CrossRefPubMedGoogle Scholar
  16. Faraut-Gambarelli F, Piarroux R, Deniau M, Giusiano B, Marty P, Michel G, Faugere B, Dumon H (1997) In vitro and in vivo resistance of leishmania infantum to meglumine antimoniate: study of 37 strains collected from patients with visceral leishmaniasis. Antimicrob Agents Chemother 41:827–830PubMedCentralPubMedGoogle Scholar
  17. Finney JD (1971) Probit Analysis, 3rd edn. Cambridge University Press, CambridgeGoogle Scholar
  18. Gupta M, Purnima B (2007) Tetrabutylammoniumbromide mediated Knoevenagel condensation in water: synthesis of cinnamic acids. ARKIVOC 1:94–98Google Scholar
  19. Handman E (1999) Cell biology of Leishmania. Adv Parasitol 44:1–39CrossRefPubMedGoogle Scholar
  20. Hung C, Tsai W, Kuo LY, Kuo Y (2005) Evaluation of caffeic acid amide analogues as anti-platelet aggregation and anti-oxidative agents. Bioorg Med Chem 13:1791–1797CrossRefPubMedGoogle Scholar
  21. Jayaprakasam B, Vanisree M, Zhang Y, Dewitt D, Nair M (2006) Impact of alkyl esters of caffeic and ferulic acids on tumor cell proliferation, cyclooxygenase enzyme, and lipid peroxidation. J Agric Food Chem 54:5375–5381CrossRefPubMedGoogle Scholar
  22. Kikuzaki H, Hisamoto M, Hirose K, Akiyama K, Taniguchi H (2002) Antioxidant properties of ferulic acid and its related compounds. J Agric Food Chem 50:2161–2168CrossRefPubMedGoogle Scholar
  23. King PJ, Ma G, Miao W, Jia Q, McDougall BR, Reinecke MG, Cornell C, Kuan J, Kim TR, Robinson WE (1999) Structure–activity relationships: analogues of the dicaffeoylquinic and dicaffeoyltartaric acids as potent inhibitors of human immunodeficiency virus type 1 integrase and replication. J Med Chem 42:497–509CrossRefPubMedGoogle Scholar
  24. Murray HW, Berman JD, Davies CR, Saravia NG (2005) Advances in leishmaniasis. Lancet 366:1561–1577CrossRefPubMedGoogle Scholar
  25. Narasimhan B, Belsare D, Pharande D, Mourya V, Dhake A (2004) Esters, amides and substituted derivatives of cinnamic acid: synthesis, antimicrobial activity and QSAR investigations. Eur J Med Chem 39:827–834CrossRefPubMedGoogle Scholar
  26. Noriaki K, Yukari K, Kazuya I, Kyo M, Tokio F (2005) In Vitro Antibacterial, antimutagenic and anti-influenza virus activity of caffeic acid phenethyl ester. Biocontrol Sci 10:155–161CrossRefGoogle Scholar
  27. Olliaro P, Bryceson A (1993) Practical progress and new drugs for changing patterns of Leishmaniasis. Parasitol Today 9:323–328CrossRefPubMedGoogle Scholar
  28. Ouellette M, Drummelsmith J, Papadopoulou B (2004) Leishmaniasis: drugs in the clinic, resistance and new developments. Drug Resist Updat 7:257–266CrossRefPubMedGoogle Scholar
  29. Pulido SA, Muñoz DL, Restrepo AM, Mesa CV, Alzate JF, Vélez ID, Robledo SM (2012) Improvement of the green fluorescent protein reporter system in Leishmania spp. for the in vitro and in vivo screening of antileishmanial drugs. Acta Trop 122(1):36–45CrossRefPubMedGoogle Scholar
  30. Radtke OA, Foo LY, Lu Y, Kiderlen A, Kolodziej H (2003) Evaluation of sage phenolics for their antileishmanial activity and modulatory effects on interleukin-6, interferon and tumour necrosis factor-α-release in RAW 264.7 cells. Z Naturforsch C 58(5–6):395–400PubMedGoogle Scholar
  31. Rajan P, Vedernikova I, Cos P, Berghe DV, Augustynsa K, Haemersa A (2001) Synthesis and evaluation of caffeic acid amides as antioxidants. Bioorg Med Chem Lett 11:215–217CrossRefPubMedGoogle Scholar
  32. Robledo SM, Valencia AZ, Saravia NG (1999) Sensitivity to Glucantime of Leishmania Viannia isolated from patients prior to treatment. J Parasitol 85:360–366CrossRefPubMedGoogle Scholar
  33. Robledo S, Osorio E, Jaramillo L (2005) In vitro and in vivo cytotoxicities and antileishmanial activities of thymol and hemisynthetic derivatives. Antimic Agents Chemoth 49:1652–1655CrossRefGoogle Scholar
  34. Son S, Lewis BA (2002) Free radical scavenging and antioxidative activity of caffeic acid amide and ester analogues: structure–activity relationship. J Agric Food Chem 50:468–472CrossRefPubMedGoogle Scholar
  35. Taylor VM, Muñoz DL, Cedeño DL, Vélez ID, Jones MA, Robledo SM (2010) Leishmania tarentolae: utility as an in vitro model for screening of antileishmanial agents. Exp Parasitol 126:471–475CrossRefPubMedGoogle Scholar
  36. Taylor VM, Cedeño DL, Muñoz DL, Jones MA, Lash TD, Young AM, Constantino MH, Esposito N, Vélez ID, Robledo SM (2011) In vitro and vivo studies of the utility of dimethyl and diethyl carbaporphyrin ketals in treatment of cutaneous leishmaniasis. Antimicrob Agents Chemother 55(10):4755–4764PubMedCentralCrossRefPubMedGoogle Scholar
  37. Valenta C, Schwarz E, Bernkop-Schnurch A (1998) Lysozyme-caffeic acid conjugates: possible novel preservatives for dermal formulations. Int J Pharm 174:125–132CrossRefGoogle Scholar
  38. Varela MRE, Muñoz DL, Robledo SM, Kolli BK, Dutta S, Chang KP, Muskus C (2009) Leishmania (Viannia) panamensis: an in vitro assay using the expression of GFP for screening of antileishmanial drug. Exp Parasitol 122:134–139PubMedCentralCrossRefGoogle Scholar
  39. Weninger B, Robledo S, Arango G, Deharo E, Aragón R, Muñoz V, Callapa J, Lobstein A, Anton R (2001) Antiprotozoal activities of Colombian plants. J Ethnopharmacol 78:193–200CrossRefGoogle Scholar
  40. Wolday D, Berhe N, Akuffo H, Britton S (1999) Leishmania-HIV interation: immunopathogenic mechanism. Parasitol Today 15:182–187CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Elver Otero
    • 1
  • Sara M. Robledo
    • 2
    • 3
  • Santiago Díaz
    • 4
  • Miguel Carda
    • 4
  • Diana Muñoz
    • 3
  • Julian Paños
    • 4
  • Ivan D. Vélez
    • 2
    • 3
  • Wilson Cardona
    • 1
    Email author
  1. 1.Química de Plantas Colombianas, Instituto de Química, Facultad de Ciencias Exactas y NaturalesUniversidad de Antioquia (UdeA)MedellínColombia
  2. 2.Programa de Estudio y Control de Enfermedades Tropicales (PECET), Sede de Investigación Universitaria (SIU)Universidad de Antioquia (UdeA)MedellínColombia
  3. 3.CIDEPRO-Center for Development of Products against Tropical DiseasesMedellínColombia
  4. 4.Departamento de Química Inorgánica y OrgánicaUniversidad Jaume ICastellónSpain

Personalised recommendations